Several experimental tumors initiate a counter-immunosurveillance mechanism that undermines the ability of the immune system to control tumor growth. Such counter-immunosurveillance is initiated by tumor-activated NKT cells that produce IL-13 and therefore signal Gr-1+ cells (monocytic or neutrophilic cell) to produce TGF-&#946;1, a cytokine that then suppresses the activity of cytolytic CD8+ T cells that would otherwise inhibit tumor growth. In the present studies we showed that in two tumor models (the CT-26 metastatic colon cancer and the 15-12RM fibrosarcoma regressor models) this counter-surveillance mechanism requires the expression of a second IL-13 receptor, IL-13R&#945;2, on CD11bhighGr-1intermediate cells: down-regulation of IL-13R&#945;2 receptor expression or the AP-1 signal generated by the receptor via in vivo administration of specific siRNA or decoy oligonucleotides leads to loss of TGF-&#946;1 production. Furthermore, from our prior studies showing that IL-13R&#945;2 expression was induced (in part) by TNF-&#945;, we demonstrated that IL-13R&#945;2 receptor expression and TGF- &#946;1 production is inhibited by administration of a TNF-&#945; neutralizing agent, TNF-&#945;R-Fc (etanercept). Taking advantage of this latter fact, we then demonstrated in the CT-26 model that counter-immunosurveillance could be inhibited, anti-CT-26-specific CD8+ cytolytic activity restored, and CT-26 metastatic tumor nodules greatly decreased by administration of TNF-&#945;R-Fc. Corroborative data was obtained using the 15-12RM fibrosarcoma model. These studies point to the prevention of metastatic cancer with an available agent having minimal toxicity.